Review
Blockade of the renin–angiotensin–aldosterone system (RAAS) for primary prevention of non-valvular atrial fibrillation: A systematic review and meta analysis of randomized controlled trials

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Abstract

Background

The renin–angiotensin–aldosterone system is suggested to play a key role in the development of atrial fibrillation through structural and electrical remodeling. This review aims to assess the effectiveness of blockade of the renin–angiotensin–aldosterone system in the prevention of new onset atrial fibrillation.

Methods

Electronic databases from 1984 onwards and previous systematic reviews were searched in addition to contacting experts in the field. Two reviewers independently selected eligible randomized controlled trials that reported on new onset atrial fibrillation, and that compared at least one of the following drugs: angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers, and aldosterone antagonists with conventional therapy or placebo.

Results

Fourteen trials including 92,817 randomized patients met the inclusion criteria. RAAS inhibition compared with conventional therapy or placebo reduced new onset atrial fibrillation (RR = 0.79; 95% CI; 0.69–0.90, p-value < 0.001). ARBs showed a strong effect in the reduction of onset atrial fibrillation (RR = 0.78; 95% CI: 0.66–0.92, p-value = 0.009), whereas results for ACE inhibitors were not as clear but likely show no effect (RR = 0.79, 95% CI: 0.62–1:00, p-value: 0.05). Aldosterone antagonists, did not appear to play a role in the prevention of new onset atrial fibrillation (RR = 0.77, 95%CI: 0.55–1.08, p-value: 0.21). Risk reduction was highest among heart failure patients.

Conclusions

RAAS inhibition appears to reduce the risk of developing new onset atrial fibrillation in different patient groups with coronary artery disease. Yet these results were considered of low quality evidence and therefore further research with stronger quality trials is required to confirm current results.

Introduction

Atrial fibrillation is the most common type of arrhythmia and is associated with an increased risk of stroke, heart failure and death [1]. The renin–angiotensin–aldosterone system (RAAS) is suggested to play a key role in the development of atrial fibrillation through structural and electrical remodeling but the exact mechanism remains unclear [2].

A number of trials investigated the effectiveness of angiontensin-converting enzyme inhibitors (ACEIs) [4,13], angiotensin-II receptor blockers (ARBs) [12], and aldosterone antagonists [5,9] in reducing atrial fibrillation with inconsistent results. Clinical guidelines described the potential role of RAAS blockade for the reduction of atrial fibrillation recurrence but provide no specific class recommendations. Further, no recommendation is provided regarding the prevention of new onset atrial fibrillation in different cardiovascular disease patients at high risk. A number of meta-analyses were conducted on this topic as this area is continuously evolving and evidence is being updated accordingly [2], [6], [3]. These reviews indicated statistically significant reduction in the rate of atrial fibrillation among patients with heart failure [2], [6], [3]. None of the reviews focused on new onset atrial fibrillation and it was not clear if ACE inhibitors and ARBs had different effects on the prevention of new onset atrial fibrillation [6]. Further, previously published reviews did not include trials that used aldosterone antagonists.

The objective of this meta-analysis is to investigate ACEIs, ARBs, or aldosterone antagonists compared with conventional therapy or placebo on the prevention of new-onset atrial fibrillation. In addition to examining the overall results, this review also explored the impact of RAAS inhibition across different patient populations (heart failure, myocardial infarction, coronary artery disease/ cardiovascular risk factors) and drug classes (ACEIs, ARBs and aldosterone antagonists).

Section snippets

Search strategy

Methods of the analysis and inclusion criteria were specified in advance and documented in a published protocol in the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42011001125 (http://www.crd.york.ac.uk/prospero/).

The following bibliographic databases were searched through Ovid interface: MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to January 2011), EMBASE (from 1948 to January 2011), and The Cochrane

Study selection

A total of 14 trials were identified for inclusion in the review, 3 of which have not been included in previous meta-analyses [2], [3], [6]. The search of Medline, Embase, and CENTRAL databases provided a total of 3861 citations. Two more citations were added through content experts and going through ACC meeting abstracts. After adjusting for duplicates 3593 trials remained. Of these, 3531 studies were discarded because after reviewing the titles and/or abstracts these papers clearly did not

Summary of results

The pooled estimate indicated an overall 21% reduction of new onset atrial fibrillation due to RAAS inhibition. Two previous meta-analyses presented results separately for new onset atrial fibrillation [6]. The current Meta-analyses included 3 more trials [17], [16], and showed similar overall reduction in atrial fibrillation. It is important to note that of these three new trials included in this systematic review, one included only 91 patients [17] and the other two had relatively short

Conclusions

The majority of the patient population included in these trials is already on anti hypertensive medication, most of which take ACE inhibitors or ARBs. Results from this review suggest an added benefit to these drug classes in addition to aldosterone antagonists in the prevention of atrial fibrillation. Patients with heart failure are most likely to benefit from these medications. Due to the low quality of evidence these results should be taken with caution until stronger evidence is generated.

Conflict of interest statement

None declared.

Acknowledgements

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

References (20)

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